INTEGRATED STUDY OF MUSCULOSKELETAL LOSS AND RESTORATION

描述（由申请人提供）：对废用后控制肌肉骨骼恢复的机制知之甚少。然而，有证据表明，随着年龄的增长，失去的组织的恢复受损。肌肉和骨骼中的前体细胞功能随着年龄的增长而改变，这可能有助于降低恢复。本提案的目的是研究组织特异性前体细胞在大鼠后肢悬吊（HS）后骨丢失和肌肉萎缩恢复过程中的作用，并确定该过程中是否存在年龄相关差异。我们推测，随着年龄的增长，组织特异性前体细胞功能的变化会损害肌肉骨骼质量的恢复。我们的方法的优势在于，肌肉和骨骼成分将在相同的动物中进行研究，促进两个系统之间的相互作用和共同机制的整合的评估。在目标1中，我们将研究年龄的增长是否会降低HS引起的肌肉骨骼萎缩的恢复能力（通过修复）。将研究肌肉和骨损失与其恢复能力之间的时间相关性。目的2解决了骨骼和肌肉中前体细胞功能和凋亡的潜在机制是否随着衰老而改变，并有助于从体内丢失的组织中受损的恢复。在目标3中，将分离骨髓干细胞和成肌细胞，并在体外测定增殖、分化和凋亡反应，以研究这些过程中的年龄相关变化是否有助于肌肉骨骼质量的萎缩和受损恢复。我们的初步数据表明，改变BMP信号的年龄依赖性作用，这可能是骨骼恢复能力减弱的原因。将确定BMP是否是老化和废用过程中骨和肌肉调节的机制基础的共同靶点。最后，在目标4中，我们将在体外和体内研究胰岛素样生长因子（IGF）-1途径的变化是否参与肌肉骨骼质量随年龄增长的受损恢复。总之，这些研究将提供重要的洞察力的细胞机制受损的能力，老年动物恢复废用后的肌肉骨骼完整性。我们已经证明的研究肌肉和骨骼的综合方法将使我们能够阐明衰老过程中肌肉骨骼系统反应性的共同机制。与公共卫生的相关性：随着年龄的增长，肌肉和骨量的损失也会增加，目前还不清楚老年人的肌肉骨骼系统在废用后的恢复能力是否会有所不同。在这项研究中，我们将确定祖细胞功能与年龄相关的变化的共同机制。确定这些影响肌肉和骨骼完整性的共同途径可能会导致药理学或治疗干预的推定目标。

DESCRIPTION (provided by applicant): Mechanisms controlling musculoskeletal recovery following disuse are poorly understood. However, there is evidence that the restoration of lost tissue is impaired with aging. Precursor cell function in both muscle and bone is altered with advancing age, which may contribute to the decreased recovery. The goal of this proposal is to investigate the role of tissue-specific precursor cells during the recovery from bone loss and muscle atrophy in response to hind-limb suspension (HS) in rats, and to determine whether there are age- associated differences in this process. We hypothesize that changes in the function of tissue-specific precursor cells impair the restoration of musculoskeletal mass with advancing age. The strength of our approach is that both muscle and skeletal components will be studied in the same animals, facilitating evaluation of the interaction between the two systems and the integration of common mechanisms. In Aim 1, we will investigate whether advancing age decreases the capacity to recover (by reambulation) the musculoskeletal atrophy induced by HS. The temporal correlation between loss of muscle and bone and their capacity for restoration will be investigated. Aim 2 addresses whether the underlying mechanisms of precursor cell function and apoptosis in bone and muscle are changed with aging and contribute to the impaired recovery from lost tissue in vivo. In Aim 3, bone marrow stem cells and myoblasts will be isolated, and proliferation, differentiation, and apoptotic responses in vitro determined to investigate whether age- associated changes in these processes contribute to atrophy and impaired restoration of musculoskeletal mass. Our preliminary data suggest an age-dependent role for altered BMP signaling, that may account for diminished restorative capacity in bone. Whether BMP is a common target underlying the mechanistic basis of bone and muscle regulation during aging and disuse will be determined. Finally, in Aim 4 we will investigate in vitro and in vivo whether changes in the insulin-like growth factor (IGF)-1 pathway are involved in the impaired restoration of musculoskeletal mass with aging. Together, these studies will provide important insight into the cellular mechanisms underlying the impaired ability of older animals to recover musculoskeletal integrity after disuse. Our proven integrative approach for studying muscle and bone will enable us to elucidate common mechanisms underlying the responsiveness of the musculoskeletal system during aging. Relevance to public health: Advancing age is associated with a loss of muscle as well as bone mass and it is unknown whether the musculoskeletal system in older individuals differs in its restorative capacity after periods of disuse. In this study we will identify common mechanisms underlying age-related changes in progenitor cell function. Identifying these common pathways influencing muscle and bone integrity could lead to putative targets for pharmacologic or therapeutic interventions.